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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/32829

Title: Aberrations in Cytokine Signaling in Leukemia: Variations in Phosphorylation and O-GlcNAcylation
Authors: Tomic, Jelena
Advisor: Spaner, David
Department: Medical Biophysics
Keywords: Chronic Lymphocytic Leukemia
Immunogenicity
Interferon (IFN)
Signal Transducer and Activator of Transcription (STAT) 1
STAT3
Reactive Oxygen Species (ROS)
Tumor suppressor p53
phosphatases
Toll-like receptor (TLR)-7 agonist
phorbol esters
immunosuppressive cytokines
O-GlcNAc
Hexosamine Biosynthetic Pathway (HBP)
Glucosamine
Resveratrol
Friend Erythroleukemia
RL2 antibody
cancer vaccines
IL-2
tumor immunosuppression
phosphorylation
O-GlcNAcylation
cytotoxic T lymphocytes (CTLs)
Ataxia telangiectasia mutated (ATM)
Antigen presenting cell (APC)
Immunotherapy
OGT
OGase
glucose
tumor metabolism
PKC
CD83
Warburg effect
tumor microenvironment
IL-10
tumor-reactive T cells
Issue Date: 31-Aug-2012
Abstract: Tumor-induced immunosuppression can occur by multiple mechanisms, each posing a significant obstacle to immunotherapy. Evidence presented in this dissertation suggests that aberrant cytokine signaling, as a result of altered metabolism of Chronic Lymphocytic Leukemia (CLL) cells, confers a selective advantage for tumor survival and growth. Cells from CLL patients with aggressive disease (as indicated by high-risk cytogenetics) were found to exhibit prolongation in Interferon (IFN)-induced STAT3 phosphorylation, and increased levels of reactive oxygen species (ROS) in these cells reflected these signaling processes. Changes in the relative balance of phospho-STAT3 and phospho-STAT1 levels, in response to combinations of IL-2 + Toll-like receptor (TLR)-7 agonist + phorbol esters, as well as IFN, were associated with the immunosuppressive and immunogenic states of CLL cells. In addition, immunosuppressive leukemic cells were found to express high levels of proteins with O-linked N-acetylglucosamine (O-GlcNAc) modifications, due to increased metabolic activity through the Hexosamine Biosynthetic Pathway (HBP), which caused impaired intracellular signaling responses and affected disease progression. A conclusion of the studies presented here is that the intrinsic immunosuppressive properties of leukemic cells may be overcome by agents such as Resveratrol that target metabolic pathways of these cells.
URI: http://hdl.handle.net/1807/32829
Appears in Collections:Doctoral

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